Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-Related Macular Degeneration Subtypes

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2×10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3×10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4×10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Seven new loci associated with age-related macular degeneration

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P <5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P <5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Structural-Functional Studies of Burkholderia cenocepacia D-Glycero-beta-D-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties

As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of D-glycero-beta-D-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors.

A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD)

Age-related macular degeneration (AMD) is the leading cause of blindness among white caucasians over the age of 50 years with a prevalence rate expected to increase markedly with an anticipated increase in the life span of the world population. To further expand our knowledge of the genetic architecture of the disease, we pursued a candidate gene approach assessing 25 genes and a total of 109 variants. Of these, synonymous single nucleotide polymorphism (SNP) rs17810398 located in death-associated protein-like 1 (DAPL1) was found to be associated with AMD in a joint analysis of 3,229 cases and 2,835 controls from five studies [combined P ADJ = 1.15 × 10(-6), OR 1.332 (1.187-1.496)]. This association was characterized by a highly significant sex difference (P diff = 0.0032) in that it was clearly confined to females with genome-wide significance [P ADJ = 2.62 × 10(-8), OR 1.541 (1.324-1.796); males: P ADJ = 0.382, OR 1.084 (0.905-1.298)]. By targeted resequencing of risk and non-risk associated haplotypes in the DAPL1 locus, we identified additional potentially functional risk variants, namely a common 897-bp deletion and a SNP predicted to affect a putative binding site of an exonic splicing enhancer. We show that the risk haplotype correlates with a reduced retinal transcript level of two, less frequent, non-canonical DAPL1 isoforms. DAPL1 plays a role in epithelial differentiation and may be involved in apoptotic processes thereby suggesting a possible novel pathway in AMSaveD pathogenesis.

Towards a general framework for social media research using big data

The increasing adoption of cloud computing, social networking, mobile and big data technologies provide challenges and opportunities for both research and practice. Researchers face a deluge of data generated by social network platforms which is further exacerbated by the co-mingling of social network platforms and the emerging Internet of Everything. While the topicality of big data and social media increases, there is a lack of conceptual tools in the literature to help researchers approach, structure and codify knowledge from social media big data in diverse subject matter domains, many of whom are from nontechnical disciplines. Researchers do not have a general-purpose scaffold to make sense of the data and the complex web of relationships between entities, social networks, social platforms and other third party databases, systems and objects. This is further complicated when spatio-temporal data is introduced. Based on practical experience of working with social media datasets and existing literature, we propose a general research framework for social media research using big data. Such a framework assists researchers in placing their contributions in an overall context, focusing their research efforts and building the body of knowledge in a given discipline area using social media data in a consistent and coherent manner.